Method for producing 5-(1-piperazinyl) -benzofuran-2-carboxamide by transition metal-catalyzed amination

ABSTRACT

1. Process for the preparation of 5-(1-piperazinyl)benzofuran-2-carboxamide in which, as intermediate step, 5-bromosalicylaldehyde or one of its derivatives is reacted in a transition metal-catalysed amination with R 2 -piperazine, in which R 2  is as defined in claim 1.

[0001] The invention relates to a process for the preparation of5-(1-piperazinyl)benzofuran-2-carboxamide, characterized in that

[0002] a) 5-bromosalicylaldehyde is reacted in a one-pot reactionfirstly with a compound of the formula I

L—CH₂—COOR¹   I

[0003]  in which

[0004] L is Cl, Br, I or a reactively esterified OH group, and

[0005] R¹ is alkyl having 1-6 carbon atoms or benzyl,

[0006] and subsequently with formamide to give5-L-benzofuran-2-carboxamide (II), in which L is Cl, Br, I or areactively esterified OH group,

[0007] (II) is then reacted in a transition metal-catalysed aminationwith R²-piperazine, in which R² is H or an amino protecting group, togive the compound of the formula III

[0008]  in which R² is H or an amino protecting group,

[0009] and subsequently, if R²≠H, R² is cleaved off,

[0010] or

[0011] b) a compound of the formula IV

[0012]  in which

[0013] L is Cl, Br, I or a reactively esterified OH group,

[0014] R³ is H or CH₂R⁶,

[0015] R⁴ and R⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷or SR⁸,

[0016] R⁴ and R⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂,═N—C(R⁸)₂, ═N—OH, ═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—,

[0017] R⁶ is CN, COOH, COOR⁷ or CONH₂,

[0018] R⁷ is alkyl having 1-6 carbon atoms,

[0019] R⁸ is phenyl which is unsubstituted or mono- or disubstituted byR⁷, OR⁷, SR⁷ or Hal,

[0020] n is 2 or 3,

[0021] is reacted in a transition metal-catalysed amination withR²-piperazine, in which R² is H or an amino protecting group,

[0022] to give a compound of the formula V

[0023]  in which

[0024] R² is H or an amino protecting group,

[0025] R³ is H or CH₂R⁶,

[0026] R⁴ and R⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷or SR⁸,

[0027] R⁴ and R⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂,═N—C(R⁸)₂, ═N—OH, ═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—,

[0028] R⁶ is CN, COOH, COOR⁷ or CONH₂,

[0029] R⁷ is alkyl having 1-6 carbon atoms,

[0030] R⁸ is phenyl which is unsubstituted or mono- or disubstituted byR⁷, OR⁷, SR⁷ or Hal,

[0031] n is 2 or 3,

[0032] which is subsequently reacted in a one-pot reaction firstly witha compound of the formula I

L—CH₂—COOR¹   I

[0033]  in which

[0034] L is Cl, Br, I or a reactively esterified OH group, and

[0035] R¹ is alkyl having 1-6 carbon atoms or benzyl,

[0036] and subsequently with formamide to give a compound of the formulaIII

[0037] in which R² is H or an amino protecting group,

[0038] and subsequently, if R²≠H, R² is cleaved off,

[0039] or

[0040] c) a compound of the formula V

[0041] in which

[0042] R² is an amino protecting group,

[0043] R³ is H or CH₂R⁶,

[0044] R⁴ and R⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷or SR⁸,

[0045] R⁴ and R⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂,═N—C(R⁸)₂, ═N—OH, ═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—,

[0046] R⁶ is CN, COOH, COOR⁷ or CONH₂,

[0047] R⁷ is alkyl having 1-6 carbon atoms,

[0048] R⁸ is phenyl which is unsubstituted or mono- or disubstituted byR⁷, OR⁷, SR⁷ or Hal,

[0049] n is 2 or 3,

[0050] is reacted with chloroacetamide to give a compound of the formulaIII

[0051] in which R² is an amino protecting group,

[0052] and R² is subsequently cleaved off,

[0053] and/or in that 5-(1-piperazinyl)benzofuran-2-carboxamide isconverted into one of its acid-addition salts by treatment with an acid.

[0054] The invention also relates to the compounds of the formula V

[0055] in which

[0056] R² is H or an amino protecting group,

[0057] R³ is H or CH₂R⁶,

[0058] R⁴ and R⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷or SR⁸,

[0059] R⁴ and R⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂,═N—C(R⁸)₂, ═N—OH, ═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—,

[0060] R⁶ is CN, COOH, COOR⁷ or CONH₂,

[0061] R⁷ is alkyl having 1-6 carbon atoms,

[0062] R⁸ is phenyl which is unsubstituted or mono- or disubstituted byR⁷, OR⁷, SR⁷ or Hal,

[0063] n is 2 or 3,

[0064] and salts and solvates thereof.

[0065] 5-(1-piperazinyl)benzofuran-2-carboxamide is an importantintermediate for pharmaceutical active ingredients. This is described,for example, in DE 19730989, WO 9857953, EP 738722, EP 736525, DE4414113, DE 4333254 or DE 4101686.

[0066] Benzofuran derivatives as precursors are also described, forexample, in DE 19514567.

[0067] Processes are known for the preparation of heterocyclic aromaticamines or arylamines, for example from EP 0 802 173, in which atransition-metal catalyst is used.

[0068] General amination reactions are described in a review article byJ. F. Martinez in Angew, Ch. Int. 37, 2046-2062. Other processes for thepreparation of tertiary arylamines using a catalyst composed of atrialkylphosphine and palladium are disclosed in JP 10-310561 (Kokaiapplication), Appl. No. 9-119477 or JP 11-80346 (Kokai application),Appl. No. 9-245218.

[0069] A process for the preparation of arylamines with transition-metalcatalysis has been described by S. L. Buchwald et al. in U.S. Pat. No.5,576,460. Another process for the preparation of aromatic amines fromchlorinated aromatic compounds in the presence of a palladium catalystis described in EP 0 846 676, by J. F. Hartwig et al. in J. Org. Chem.1999, pp. 5575-5580, or S. L. Buchwald et al. in J.A.C.S. 1999, 121,9550-9561.

[0070] In Tetrahedron Letters 39 (1998) 617-620, M. Nishiyama describesthe synthesis of N-arylpiperazines from aryl halides and piperazine withtransition-metal catalysis.

[0071] Surprisingly, studies in the course of the synthesis ofmedicaments which are described, for example, in DE 43 33 254 (EP 0 648767) have shown that 5-(1-piperazinyl)benzofuran-2-carboxamide can beobtained in at least comparable or higher overall yield compared withthe prior art, crucial advantages which may be mentioned here being thefact that the reaction is simple to carry out and product isolation isconsequently simple.

[0072] Another consequence of this is the low solvent and energyconsumption.

[0073] If L in the compounds of the formulae I, II or IV is a reactivelyesterified OH group, this is preferably alkylsulfonyloxy having 1-6carbon atoms (preferably methylsulfonyloxy ortrifluoromethylsulfonyloxy), arylsulfonyloxy having 6-10 carbon atoms(preferably phenyl- or p-tolylsulfonyloxy, furthermore also2-napthalenesulfonyloxy) or alternatively fluorosulfonyloxy.

[0074] R¹ is alkyl or benzyl. Alkyl here has 1, 2, 3, 4, 5 or 6 carbonatoms, preferably 1, 2, 3 or 4 carbon atoms, particularly preferably,for example, methyl or ethyl, furthermore propyl, isopropyl, furthermorealso butyl, isobutyl, sec-butyl or tert-butyl.

[0075] In the compounds of the formula I, L is preferably Cl,furthermore also Br.

[0076] R² is H or an amino protecting group. R² is particularlypreferably an amino protecting group.

[0077] The term “amino protecting group” is known in general terms andrefers to groups which are suitable for protecting (blocking) an aminogroup against chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical such groups are, in particular, unsubstituted acyl,aryl, aralkoxymethyl or aralkyl groups. Since the amino protectinggroups are removed after the desired reaction (or reaction sequence),their type and size are furthermore not crucial; however, preference isgiven to those having 1-20, in particular 1-8, carbon atoms. The term“acyl group” in connection with the present process and the presentcompounds should be understood in the broadest sense. It covers acylgroups derived from aliphatic, araliphatic, aromatic or heterocycliccarboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acylgroups of this type are alkanoyl, such as acetyl, propionyl, butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as, benzoyl or tolyl;aryloxyalkanoyl, such as phenoxyacetyl; alkoxycarbonyl, such asmethoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC(tert-butoxycarbonyl), 2-iodoethoxycarbonyl; aralkyloxycarbonyl, such asCBZ (carbobenzoxycarbonyl), also referred to as “Z”),4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxycarbonyl);arylsulfonyl, such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl).

[0078] R² is very particularly preferably benzyl or BOC.

[0079] An amino protecting group can be removed from a compound of theformula III—depending on the protecting group used—using, for example,strong acids, advantageously using TFA (trifluoroacetic acid) orperchloric acid, but also using other strong inorganic acids, such ashydrochloric acid or sulfuric acid, strong organic carboxylic acids,such as trichloroacetic acid, or sulfonic acids, such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible, but is not always necessary. Suitable inert solvents arepreferably organic solvents, for example carboxylic acids, such asacetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such asdimethylformamide, halogenated hydrocarbons, such as dichloromethane,furthermore also alcohols, such as methanol, ethanol or isopropanol, andwater. Also suitable are mixtures of the above-mentioned solvents. TFAis preferably used in excess without addition of a further solvent, andperchloric acid is preferably used in the form of a mixture of aceticacid and 70% perchloric acid in the ratio 9:1. The reaction temperaturesare advantageously between about 0 and about 50°, preferably between 15and 30°. The BOC group is preferably cleaved off using TFA indichloromethane or using approximately 3 to 5N hydrochloric acid indioxane at 15-30°.

[0080] Protecting groups which can be removed hydrogenolytically (forexample CBZ or benzyl) can be cleaved off, for example, by treatmentwith hydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those mentioned above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° and pressures between about 1 and200 bar, preferably at 20-30° and 1-10 bar.

[0081] R³ is preferably H.

[0082] R³ and R⁴ are preferably methoxy, ethoxy, propoxy or phenoxy.

[0083] R⁴ and R⁵ are in particular together carbonyl.

[0084] In the compounds of the formula IV, Hal is preferably Br.

[0085] The compounds of the formula IV and V can also be in dimeric formwhich can be cleaved back to the corresponding salicylaldehydes, inwhich L and R² have the meanings indicated:

[0086] R⁷ is alkyl. Alkyl here has 1, 2, 3, 4, 5 or 6 carbon atoms,preferably 1, 2, 3 or 4 carbon atoms, particular preference being given,for example, to methyl or ethyl, furthermore propyl, isopropyl,furthermore also butyl, isobutyl, sec-butyl or tert-butyl.

[0087] In the compounds of the formulae IV and V,

[0088] ═N—C(R⁷)₂ is preferably ═N—C(CH₃)₂,

[0089] ═N—C(R⁸)₂ is preferably ═N—C(phenyl)₂,

[0090] ═N—OR⁷ is preferably ═N—OCH₃,

[0091] ═N—N[(R⁷)₂] is preferably ═N—N[(CH₃)₂],

[0092] ═N—N[(R⁸)₂] is preferably ═N—N[(phenyl)₂].

[0093] The compounds of the formulae I and IV are either known or areotherwise prepared by methods known per se, as described in theliterature (for example in the standard works, such as Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry],Georg-Thieme Verlag, Stuttgart), to be precise under reaction conditionswhich are known and suitable for said reactions. Use can also be madehere of variants which are known per se, but are not mentioned here ingreater detail.

[0094] Process Variant a)

[0095] The reaction of 5-bromosalicylaldehyde with a compound of theformula I and subsequently with formamide is carried out as a one-potreaction in a suitable inert solvent with addition of a base.

[0096] Examples of suitable inert solvents are hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane, ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); carbon disulfide; nitro compounds, such asnitromethane or nitrobenzene; optionally also mixtures of said solventswith one another.

[0097] The reaction time, depending on the conditions used, is between afew minutes and 14 days, and the reaction temperature is between about0° and 150°, preferably between 60° and 120°.

[0098] The reaction time is very particularly preferably between 4 and20 hours and the temperature between 90 and 115°.

[0099] Suitable bases are compounds such as, for example, Na, K or Cscarbonate.

[0100] A one-pot reaction is subsequently carried out with formamide,preferably in the presence of an organic base, preferably an alkalimetal alkoxide, such as, for example, Na tert-butoxide, and itscorresponding alcohol, to give 5-Hal-benzofuran-2-carboxamide (II). In(II), Hal is preferably Br.

[0101] The reaction is preferably carried out at from 0 to 60°.

[0102] Other processes to give (II) are described, for example, in Bull.Soc. Chim. Fr., 1971; 4329, and by O. Dann et al. in Justus Liebigs Ann.Chem. 1975; 160-194. The one-pot reaction described above proceeds inbetter yield than said reactions.

[0103] The reaction of (II) with R² -piperazine to give the compound ofthe formula III is carried out in a suitable inert solvent, a base andin the presence of a transition-metal catalyst.

[0104] Transition metals which can be employed include PdCl₂ or Pd(OAc)₂or other Pd²⁺ derivatives, which are pre-reduced, for example usingNaBH₄ or phosphines (the step can be omitted in the case of an excess ofligand R₃P) or Pd(0) species, such as, for example, Pd(DBA)₂ orPd₂(DBA)₃ (DBA=dibenzylideneacetone)

[0105] To this range of Pd complexes can be added corresponding ligandcomplexes of nickel or copper.

[0106] Furthermore, ligands which can be employed areN,N-diarylimidazolium salts analogously to J. Huang et al., Org. Lett.1, 1999, 1307-1309.

[0107] The phosphine or aza/phosphine ligands employed include

[0108] tris-ortho-tolylphosphine

[0109] tricyclohexylphosphine

[0110] 1-(2-diphenylphosphino-1-naphthyl)isoquinoline (QUINAP)

[0111] 1,8-bis(dimethylamino)naphthalene

[0112] Phe₂P—CH₂—PPhe₂

[0113] in particular also P(tert-butyl)₃=P(t-Bu)₃

[0114] 1,1′-bis(diphenylphosphano)ferrocene (DPPF as complex DPPFxPdCl₂)

[0115] 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (=BINAP)(S)-dibutphos=1-(2-di-tert-butylphosphanylphenyl)ethyldimethylamine

[0116] 1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl

[0117] 1-(di-t-butylphosphino)biphenyl

[0118] 1,1′-bis(di-t-butylphosphino)biphenyl

[0119] (t-Bu)₂P—(CH₂)_(n)—P(t-Bu)₂ n=1,2,3

[0120] (t-Bu)₂P—(CH₂)_(m)—X—(CH₂)_(n)—P(t-Bu)₂ m,n=1, 2, 3; X=O, . . .

[0121] or alternatively

[0122] DB^(t)PF=1,1′-bis(di-tert-butylphosphino)ferrocene.

[0123] Examples of suitable solvents are hydrocarbons, such as benzene,toluene, xylene; chlorinated hydrocarbons, such as, for example,dichloromethane; ketones, such as acetone, butanone; ethers, such astetrahydrofuran (THF) or dioxane; nitriles, such as acetonitrile,optionally also mixtures of these solvents with one another.

[0124] The reaction time, depending on the conditions used, is between afew minutes and 14 days, and the reaction temperature is between 0° and180°, normally between 30° and 130°.

[0125] Examples of suitable bases are alkali metal alkoxides, such as,for example, Na tert-butoxide.

[0126] Process Variant b)

[0127] The reaction of compounds of the formula IV with R²-piperazine iscarried out under conditions as described under variant a).

[0128] R⁴ and R⁵ are optionally converted into a carbonyl group. Thesubsequent one-pot reaction of the compound of the formula V with thecompound of the formula I and subsequently with formamide is likewisecarried out under conditions as described above. The elimination of R²,if R²≠H, is also carried out under the conditions described.

[0129] A base of the formula I or of the formula V can be converted intothe associated acid-addition salt by means of an acid, for example byreaction of equivalent amounts of the base and the acid in an inertsolvent, such as ethanol, followed by evaporation. Particularly suitableacids for this reaction are those which give physiologically acceptablesalts. Thus, it is possible to use inorganic acids, for example sulfuricacid, nitric acid, hydrohalic acids, such as hydrochloric acid orhydrobromic acid, phosphoric acids, such as orthophosphoric acid,sulfamic acid, furthermore organic acids, in particular aliphatic,alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasiccarboxylic, sulfonic or sulfuric acids, for example formic acid, aceticacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid,tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,laurylsulfuric acids. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

[0130] Above and below, all temperatures are given in ° C. In theexamples below, “conventional work-up” means that water is added ifnecessary, the pH is adjusted to between 2 and 10 if necessary,depending on the constitution of the end product, the product isextracted with ethyl acetate or dichloromethane, the phases areseparated, the organic phase is dried over sodium sulfate andevaporated, and the product is purified by chromatography on silica geland/or by crystallization.

EXAMPLE 1 1) Synthesis of 5-bromobenzofuran-2-carboxamide

[0131]

[0132] Performance of the reaction with ethyl bromoacetate: 200 g of5-bromo-2-hydroxybenzaldehyde are dissolved in 2000 ml of NMP withstirring, and 144 g of potassium carbonate and 175 g of ethylbromoacetate are added. The mixture is stirred at 105° under nitrogenfor 15 hours. The resultant orange solution dotted with crystals iscooled to 25°, 135 g of formamide are added, and the mixture is stirredfor a further 30 minutes. 557 ml of sodium methoxide (30% in MeOH) arethen allowed to run in over the course of 15 minutes without cooling.After 3 hours, a brownish solution dotted with crystals is present. Itis poured into 6 litres of demineralized water (10°), and the mixture isstirred for a further 30 minutes. The crystals are filtered off withsuction, washed with 1 litre of demineralized water, re-suspended in 4litres of demineralized water, filtered off with suction and re-washedwith 1 litre of demineralized water. The crystals are dried overnight toconstant weight under reduced pressure at 60° C. (product weight: 113 gof pale beige crystals; m.p. 210-213°; CAS 35351-21-4).

[0133] The physical and spectroscopic data correspond to the datapublished in: Rene; Royer; BSCFAS; Bull. Soc. Chim. Fr.; 1971; 4329, andDann, O. et al.; JLACBF; Justus Liebigs Ann. Chem.; GE; 1975; 160-194.

[0134] 5-Chlorobenzofuran-2-carboxamide (m.p. 200-202°),5-fluorobenzofuran-2-carboxamide and 5-iodobenzofuran-2-carboxamide canbe obtained in comparable yields using the same method.

2) Synthesis of 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide byTransition Metal-Catalysed Amination of 5-bromobenzofuran-2-carboxamideusing benzylpiperazine

[0135]

[0136] Illustrative performance using the catalyst system Pd(OAc)₂/P(t-Bu)₃:

[0137] 0.30 g of P(t-Bu)₃, 4.5 g of 5-bromobenzofuran-2-carboxamide, 4.9g of benzylpiperazine and 5.0 g of Na t-OBu are added to a suspension of0.085 g of Pd(II) acetate in 150 ml of xylene after the latter has beenstirred for 15 minutes, and the mixture is warmed at 125° C. for 12-18hours under the protective gas nitrogen. After cooling, the mixture isadded to 500 ml of 2N hydrochloric acid, and the aqueous phase isextracted 3 times with 200 ml of ethyl acetate. The aqueous phase isadjusted to pH 10 using aqueous NaOH (20%) with pH and temperaturemonitoring (20-25° C.), and the5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide produced as a solidis filtered off and crystallized, for example, from ethanol/water(product weight: 4.0 g/64%/m.p. 277-279°).

3) Synthesis of 5-(1-piperazinyl)benzofuran-2-carboxamide from5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide

[0138]

[0139] Hydrogenolysis procedure:

[0140] 5.0 g of 5-(4-benzyl-1-piperazinyl)benzofuran-2-carboxamide areadded to 300 ml of ethanol, and, after 9 g of palladium on activatedcarbon (5%) and 5 g of HOAc (100%) have been added, the product isdebenzylated to completion at 20-30° C. using hydrogen. After filtrationand removal of the solvent under reduced pressure and crystallizationfrom alcohol or water and drying at 60° C. under reduced pressure, theproduct can be isolated (3.1 g/85%/m.p. 252-255°, spectroscopicallyidentical with the material prepared by previous methods; described,inter alia, in DE 4101686/laid open Jul. 23, 1992; DE 4333254/laid openApr. 6, 1995; EP 0648767/published Apr. 19, 1995; EP 0738722/publishedOct. 23, 1996).

EXAMPLE 2 1) Synthesis of5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide from5-bromobenzofuran-2-carboxamide

[0141]

[0142] 0.9 g of 5-bromobenzofuran-2-carboxamide, 1.1 g of BOC-piperazineand 1.45 g of Na t-OBu are added to a suspension of 0.06 g of Pd(DBA)₂and 0.25 g of P(t-Bu)₃ in 40 ml of diethylene glycol dimethyl ether, andthe mixture is warmed at 120-130° C. for 16 hours under a protectivegas. After cooling, the mixture is added to water, and the organic phaseis diluted with 100 ml of MTBE and washed with 3×50 ml of water. Thesolvent is evaporated, and the product formed as a solid is filtered offand purified by crystallization from ethanol (product weight: 0.7g/55%/m.p. 210-213°).

[0143] The subsequent removal of the BOC protecting group usinghydrochloric acid and formation of5-(1-piperazinyl)benzofuran-2-carboxamide, which are shown below only asa reaction equation, can be carried out, for example, as described inGREENE T. W. and WUTS P. G. M., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS.

EXAMPLE 3 Synthesis of 5-(1-piperazinyl)benzofuran-2-carboxamide from5-bromobenzofuran-2-carboxamide

[0144]

[0145] 0.9 g of 5-bromobenzofuran-2-carboxamide, 0.97 g of piperazineand 2.20 g of Na t-OBu are added to a suspension of 0.06 g of Pd(DBA)₂and 0.07 g of 1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenylin 50 ml of toluene, and the mixture is warmed at 120-130° for 16 hoursunder a protective gas. After cooling, the reaction mixture is added toa mixture of 50 ml of water and 10 ml of 37% hydrochloric acid, 100 mlof ethyl acetate are added, and the mixture is stirred for 20 minutes. Alittle undissolved product is then removed, and the organic phase isseparated off. The aqueous phase is washed again by shaking with 50 mlof ethyl acetate and freed from solvent residues under reduced pressure,clarified using charcoal and filtered. The product is precipitated incrystalline form from the filtrate at 20-22° using 20-25 ml of 32%sodium hydroxide solution. The product is filtered off and dried(product weight: 0.65 g/70% /m.p. 252-255°).

EXAMPLE 4 1) Synthesis of5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde

[0146]

[0147] 0.6 g of bis(dibenzylideneacetone)palladium and 0.16 g oftri-tert-butylphosphine are added under nitrogen to 200 ml of toluene,and the resultant dark-red solution is stirred at 20° for 20 minutes. 10g of 5-bromo-2-hydroxybenzaldehyde, 9.7 g of 1-benzylpiperazine and 7.2g of sodium tert-butoxide are then added. The mixture is stirred at 60°for 24 hours and cooled, 800 ml of water are added, and the mixture isextracted with 2×500 ml of ethyl acetate. The organic phases arecombined and washed with 300 ml of water, and the solvent is removed at30° under reduced pressure. The dark-orange oil which remains (9.7 g) ispurified by chromatography (300 g of silica gel; MTB ether/heptane 5:1;1.5 litres). 9.9 g of pale-yellow crystals remain (67%), m.p. 101-103°;MS 296 (M+), 205, 119, 91 (100%).

2) Synthesis of ethyl 4-(4-benzylpiperazin-1-yl)-2-formylphenoxyacetate

[0148]

[0149] 0.5 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde aredissolved in 5 ml of NMP at 20° C. under nitrogen with stirring, and0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate areadded. The mixture is stirred at 110° for 4 hours and cooled to 15°. 30ml of water and 30 ml of ethyl acetate are added to the mixture, thephases are separated, and the aqueous phase is extracted with 30 ml ofethyl acetate. Combined organic phases are washed with 2×30 ml of waterand freed from solvent under reduced pressure. The yellow oil whichremains (0.7 g) is chromatographed on 10 g of silica gel (MTBether/heptane 5:1) and gives 0.45 g of product (70%; yellowish oil), MS382 (M+), 296, 263, 199, 149, 119, 91 (100%).

EXAMPLE 5 1) Synthesis of ethyl5-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate

[0150]

[0151] 0.5 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde isadded at 20° with stirring to 5 ml of NMP, and 0.25 g of potassiumcarbonate and 0.2 ml of ethyl bromoacetate are added to the solution.The mixture is stirred at 105° for 15 hours and then cooled to 25°. Thebatch is added to 30 ml of water (10°) with stirring, the aqueous phaseis extracted at 10° with 3×50 ml of ethyl acetate, and the combinedorganic phases are washed with 50 ml of water and then freed fromsolvent under reduced pressure (1.2 g of orange oil). Columnchromatography on 30 g of silica gel (MTB ether/heptane 5:1) gives 0.43g of pale-yellow crystals (71%), m.p. 105-107°; MS 364 (M+), 268, 204,146, 119, 91 (100%).

[0152] A sample of the corresponding hydrochloride (m.p. 219-222°) canbe obtained by dissolution in ethanol, addition of aqueous 1Nhydrochloric acid, isolation of the resultant solid and drying underreduced pressure.

EXAMPLE 6 1) Synthesis of5-(4-benzylpiperazin-1-yl)benzofuran-2-carboxamide

[0153]

[0154] 500 mg of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde areadded at 20° under nitrogen with stirring to 5 ml of NMP, and 0.25 g ofpotassium carbonate and 0.2 ml of ethyl bromoacetate are added to thesolution. The mixture is stirred at 105° for 15 hours and cooled to 25°.0.2 ml of formamide is then added to the mixture, and stirring iscontinued for 30 minutes. 1 ml of sodium methoxide (30% solution inmethanol) is then added at 25° over the course of 15 minutes, and themixture is stirred at 25-30° for a further 3 hours. The reaction mixtureis poured into 30 ml of water (10°), the aqueous phase is extracted at10° with 3×50 ml of ethyl acetate, the combined organic phases arewashed with 50 ml of water, and the solvent is removed under reducedpressure (0.7 g of orange oil). The oil is recrystallized from 10 ml oftoluene (375 mg of pale-yellow crystals; 66%), m.p. 206-208°; MS 335(M+), 244, 189, 146, 91 (100%).

[0155] Removal of the protecting group gives5-(1-piperazinyl)benzofuran-2-carboxamide.

EXAMPLE 7 1) Synthesis of5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde

[0156]

[0157] 0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g oftri-tert-butylphosphine are added under nitrogen to 200 ml of toluene,and the resultant solution, which becomes dark red, is stirred at 20°for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g oftert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide arethen added. The mixture is stirred at 60° for 24 hours and cooled, 800ml of water are added, and the mixture is extracted with 2×500 ml ofethyl acetate. The organic phases are combined and washed with 300 ml ofwater, and the solvent is removed at 30° under reduced pressure. Thedark-orange oil which remains (11 g) is purified by chromatography (300g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g ofpale-yellow crystals (51%), m.p. 84-86°; MS 306 (M+), 250 (100%), 233,176, 164.

2) Synthesis of ethyl4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-formylphenoxyacetate

[0158]

[0159] 0.5 g of 5-(4-tert-butoxypiperazin-1-yl)-2-hydroxybenzaldehydeare dissolved in 5 ml of NMP at 20° under nitrogen with stirring, and0.25 g of potassium carbonate and 0.2 ml of ethyl bromoacetate areadded. The mixture is stirred at 110° for 30 minutes and cooled to 25°.30 ml of water and 30 ml of ethyl acetate are added to the mixture, thephases are separated, and the aqueous phase is extracted with 30 ml ofethyl acetate. The combined organic phases are washed with 30 ml ofwater and freed from solvent under reduced pressure. 30 ml of toluene,30 ml of water and 5 ml of 1N HCl are added to the crystal slurry whichremains, the toluene phase is removed under reduced pressure, and thecrystalline precipitate is separated off and dried at 40° under reducedpressure (0.48 g; 75%), m.p. 93-94° C.; MS 392 (M+), 336 (100%),250/249, 57.

EXAMPLE 8 1) Synthesis of ethyl5-(4-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxylate

[0160]

[0161] 520 mg of5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde are addedat 20° under nitrogen with stirring to 5 ml of NMP, and 0.25 g ofpotassium carbonate and 0.2 ml of ethyl bromoacetate are added to thesolution. The mixture is stirred at 105° for 3 hours and then cooled to25°. The batch is added to 30 ml of water (10°) with stirring, theaqueous phase is extracted at 10° with 3 times 30 ml of ethyl acetate,and the combined organic phases are washed with 30 ml of saturated NaClsolution and with 30 ml of water and then freed from solvent underreduced pressure (0.6 g of orange oil with crystal components). Afterchromatography on 30 g of silica gel (MTB ether/heptane 5:1), 0.45 g ofpale-yellow crystals can be isolated (70%), m.p. 116-117°; MS 374 (M+),318 (100%), 244, 232.

EXAMPLE 9 1) Synthesis of5-(4-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxamide

[0162]

[0163] 1.04 g of5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde are addedat 20° under nitrogen with stirring to 10 ml of NMP, and 0.5 g ofpotassium carbonate and 0.4 ml of ethyl bromoacetate are added to thesolution. The mixture is stirred at 120° for 5 hours and cooled to 25°.0.4 ml of formamide is then added to the mixture, and stirring iscontinued for 30 minutes. 1.9 ml of sodium methoxide (30% solution inmethanol) are then added over the course of 15 minutes without cooling,and stirring is continued for a further hour at 25-30°. 30 ml of waterand 30 ml of ethyl acetate are added to the batch, the phases areseparated, and the aqueous phase is extracted with 30 ml of ethylacetate. The combined organic phases are washed with 30 ml of water, andthe solvent is removed under reduced pressure (1.1 g of orange crystalslurry). After crystallization using 20 ml of toluene, 500 mg ofpale-beige crystals remain. The mother liquor is evaporated, and the oilwhich remains is dissolved in 10 ml of toluene. After 3 hours at 0°,further pale-beige crystals form (identical with the first crystals; 70mg). The total yield (0.57 g) is 49%, m.p. 202-204°; MS 345 (M+), 289(100%), 272, 244, 215, 203.

[0164] The BOC group is removed as described, giving5-(1-piperazinyl)benzofuran-2-carboxamide.

EXAMPLE 10 1) Synthesis of5-(4-tert-butoxycarbonylpiperazin-1-yl)benzofuran-2-carboxamide

[0165] 5 ml of 1-methyl-2-pyrrolidone, 0.16 g of chloroacetamide and0.25 g of potassium carbonate are added at 20° C. with stirring/undernitrogen to 0.5 g of5-(4-tert-butoxycarbonylpiperazin-1-yl)-2-hydroxybenzaldehyde. Themixture is stirred at 60° C. for 16 hours, cooled and then filtered, andthe solvent is removed under reduced pressure. The residue is taken upin MTB ether, re-filtered and concentrated, and the residue iscrystallized from toluene. The isolated yield is 0.34 g (60%).

2) Synthesis of 5-(4-benzylpiperazin-1-yl)benzofuran-2-carboxamide

[0166] 10 ml of 1-methyl-2-pyrrolidone, 0.4 g of chloroacetamide and 0.8g of potassium carbonate are added at 20° C. with stirring/undernitrogen to 1.0 g of 5-(4-benzylpiperazin-1-yl)-2-hydroxybenzaldehyde.The mixture is stirred at 60° C. for 16 hours, cooled and then filtered,and the solvent is removed under reduced pressure. The residue is takenup in MTB ether, re-filtered and concentrated, and the residue iscrystallized from toluene. The isolated yield is 0.73 g (65%).

1. Process for the preparation of5-(1-piperazinyl)benzofuran-2-carboxamide, characterized in that a)5-bromosalicylaldehyde is reacted in a one-pot reaction firstly with acompound of the formula I L—CH₂—COOR¹   I  in which L is Cl, Br or I ora reactively esterified OH group, and R¹ is alkyl having 1-6 carbonatoms or benzyl, and subsequently with formamide to give5-L-benzofuran-2-carboxamide (II), in which L is Cl, Br or I or areactively esterified OH group, (II) is then reacted in a transitionmetal-catalysed amination with R²-piperazine, in which R² is H or anamino protecting group, to give the compound of the formula III

 in which R² is H or an amino protecting group, and subsequently, ifR²≠H, R² is cleaved off, or b) a compound of the formula IV

 in which L is Cl, Br, I or a reactively esterified OH group, R³ is H orCH₂R⁶, R⁴ and R⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷or SR⁸, R⁴ and R⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂,═N—C(R⁸)₂, ═N—OH, ═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n—O—,)R⁶ is CN, COOH, COOR⁷ or CONH₂, R⁷ is alkyl having 1-6 carbon atoms, R⁸is phenyl which is unsubstituted or mono- or disubstituted by R⁷, OR⁷,SR⁷ or Hal, n is 2 or 3, is reacted in a transition metal-catalysedamination with R²-piperazine, in which R² is H or an amino protectinggroup, to give a compound of the formula V

 in which R² is H or an amino protecting group, R³ is H or CH₂R⁶, R⁴ andR⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷ or SR⁸, R⁴ andR⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂, ═N—C(R⁸)₂, ═N—OH,═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—, R⁶ is CN, COOH,COOR⁷ or CONH₂, R⁷ is alkyl having 1-6 carbon atoms, R⁸ is phenyl whichis unsubstituted or mono- or disubstituted by R⁷, OR⁷, SR⁷ or Hal, n is2 or 3, which is subsequently reacted in a one-pot reaction firstly witha compound of the formula I L—CH₂—COOR¹   I  in which L is Cl, Br, I ora reactively esterified OH group, and R¹ is alkyl having 1-6 carbonatoms or benzyl, and subsequently with formamide to give a compound ofthe formula III

 in which R² is H or an amino protecting group, and subsequently, ifR²≠H, R² is cleaved off, or c) a compound of the formula V in which R²is an amino protecting group, R³ is H or CH₂R⁶, R⁴ and R⁵ are each,independently of one another, OR⁷, OR⁸, SR⁷ or SR⁸, R⁴ and R⁵ togetherare alternatively carbonyl, ═S, ═N—C(R⁷)₂, ═N—C(R⁸)₂, ═N—OH, ═N—OR⁷,═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—, R⁶ is CN, COOH, COOR⁷ orCONH₂, R⁷ is alkyl having 1-6 carbon atoms, R⁸ is phenyl which isunsubstituted or mono- or disubstituted by R⁷, OR⁷, SR⁷ or Hal, n is 2or 3, is reacted with chloroacetamide to give a compound of the formulaIII in which R² is an amino protecting group, and R² is subsequentlycleaved off, and/or in that 5-(1-piperazinyl-)benzofuran-2-carboxamideis converted into one of its acid-addition salts by treatment with anacid.
 2. Process according to claim 1, characterized in that Hal in thecompound of the formula I is Br.
 3. Process according to claim 1,characterized in that the transition-metal catalyst system used isPd(OAc)₂/P(tert-butyl)₃.
 4. Process according to claim 1, characterizedin that in the reaction of 5-bromosalicylaldehyde or a compound of theformula V with a compound of the formula I, N-methylpyrrolidone is usedas solvent.
 5. Compounds of the formula V

in which R² is H or an amino protecting group, R³ is H or CH₂R⁶, R⁴ andR⁵ are each, independently of one another, OR⁷, OR⁸, SR⁷ or SR⁸, R⁴ andR⁵ together are alternatively carbonyl, ═S, ═N—C(R⁷)₂, ═N—C(R⁸)₂, ═N—OH,═N—OR⁷, ═N—N[(R⁷)₂], ═N—N[(R⁸)₂] or —O—(CH₂)_(n)—O—, R⁶ is CN, COOH,COOR⁷ or CONH₂, R⁷ is alkyl having 1-6 carbon atoms, R⁸ is phenyl whichis unsubstituted or mono- or disubstituted by R⁷, OR⁷, SR⁷ or Hal, n is2 or 3, and salts and solvates thereof.